Kawasaki Disease

Epidemiology
Incidence

First described in 1967
1. Kawasaki (1967) Arerugi 16(3): 178-222 [PubMed]
Overall U.S.: 19 per 100,000 children <5 years (2000 U.S. cases/year)
1. Japanese descent: 150 per 100,000 children <5 years
2. Asian american children 2.5 times more likely than white children
3. Black american children 1.5 times more likely than white children
Age of onset
1. Most cases (75-80%) occur by age 5 years old
2. Peak age of onset: 1 to 2 years old
3. Rare under 4 months of age
Gender: Boys more often affected (by ratio of 1.5 to 1)
More common in winter and spring (typically between January and March)

Pathophysiology

Idiopathic Vasculitis
1. Inflammatory Cytokines (e.g. TNF, IL-6) promote Leukocyte mediated endothelial injury
Postulated associations
1. Retrovirus
2. Rickettsia

Precautions

Infants under 6 months of age often present atypically, and have the highest risk of Coronary Artery complications

Symptoms

Fever for 5 days or more
Significant Irritability

Diagnosis
Requires fever and 4 other criteria

Fever prolonged more than 5 days (100%)
1. Fever >102.2 F (often >104 F) with abrupt onset
2. Duration: Averages 11 days untreated
Polymorphous skin eruption on trunk (80-96%)
1. Starts within first five days with a 7 day duration
2. Involves extremities, trunk and perineal region
3. May appear maculopapular, scarlatina-form or Erythema Multiforme-like
4. May appear morbiliform or Urticarial
5. No bullae or vessicles
Conjunctivitis (84-89%%)
1. Bilateral Conjunctival injection (bulbar)
2. No Ciliary Flush (no limbus injection)
3. No photophobia
4. No Eye Pain
5. Non-purulent
6. May be associated with painless Anterior Uveitis
Acute Lymphadenopathy
1. Typically a single, unilateral, minimally to non-tender node >1.5 cm (73%)
2. Cervical Lymphadenopathy is most common
Changes in hands and feet
1. Edema of hands and feet - may be painful (65%)
2. Red palms and soles (69%)
  1. Sharp demarcation at ankles and wrists
3. Desquamation of fingertips (80%)
  1. Late sign occurs at 2-3 weeks after fever onset
  2. Starts at periungual area
Mucus mebrane changes (92-96%)
1. Dry, red, fissured, or vertically cracked lips
2. Strawberry Tongue (erythematous Tongue with prominent papillae)
3. Diffuse reddening of the oropharynx
4. No focal lesions, exudates, Vesicles or ulcers

Diagnosis
Alternative Criteria (met by 9.6% of cases, esp. young infants and older children)

Fever for at least 5 days AND
Two or three main criteria above (incomplete criteria) AND
Coronary Artery Abnormalities on Transthoracic Echocardiogram

Signs
Other Associated

Urethritis with sterile pyuria (75%)
Polyarthralgia
Aseptic Meningitis (25%)
Gastrointestinal Symptoms
1. Abdominal Pain and Diarrhea (25%)
2. Obstructive Jaundice with acute gallbladder hydrops
Cardiac Disease (20%)
1. Pericardial Effusion
2. Congestive Heart Failure
3. Arrhythmias
4. Mitral Regurgitation
5. Coronary Artery anomalies (see below)

Differential Diagnosis

Juvenile Rheumatoid Arthritis
Hypersensitivity Reaction
1. Medication allergy
2. Mercury Poisoning
3. Serum Sickness
4. Stevens-Johnson Syndrome
Bacterial Infection
Viral infection

Labs

Complete Blood Count with differential cell count
1. Anemia
2. Leukocytosis (>15,000/uL)
3. Thrombocytosis (>500,000/uL)
  1. Often delayed until 2-3 weeks after fever onset
Erythrocyte Sedimentation Rate >40 mm/hr (may be >100)
C-Reactive Protein (CRP) >3 mg/dl
1. Preferred (unlike ESR, CRP is not altered with IVIG administration)
Basic chemistry panel
1. Hyponatremia
Liver Function Tests
1. Increased liver enzymes (esp. serum transaminases AST and ALT, and GGT)
2. Hypoalbuminemia may predict a more prolonged, severe course
Blood Culture
Throat Culture
Antistreptolysin-O Titer (ASO Titer)
Urinalysis
1. Sterile pyuria in >33% of cases
Consider Lumbar Puncture if Meningitis suspected
1. Pleocytosis may be seen in Kawasaki's

Diagnostics

Electrocardiogram (EKG)
1. May demonstrate strain pattern (ST and T Wave changes)
Chest XRay
1. Observe for cardiomegaly
MRI Coronary Angiography
1. May be used when Echocardiogram is non-diagnostic (esp. circumflex, distal vessels)
2. May demonstrate Coronary Artery stenosis, thrombi or intimal hyperplasia

Imaging
Echocardiogram Coronary Artery evaluation

Initial Echocardiogram at presentation
Follow-up Echocardiogram at 2 weeks and 6-8 weeks
Indications for Echocardiogram at 6-12 months
1. Abnormalities on prior Echocardiograms
2. AHA guidelines currently recommend in all patients
3. However no benefit if prior Echocardiograms normal
4. Tuohy (2001) Am J Cardiol 88:328-30 [PubMed]
Findings
1. Coronary Artery changes
  1. Acute: Tapering, perivascular brightness, ectasia
  2. Late: Coronary Artery aneurysm
2. Other variable changes
  1. Decreased ventricular function
  2. Pericardial Effusion

Evaluation

Diagnostic criteria met (five days of fever and 4 of the 5 other findings present)
1. Treat as Kawasaki Disease
2. May also treat at 4 days if criteria otherwise met
3. Also see alternative criteria listed above
Diagnostic criteria not met (five days of fever with only 2-3 other findings)
1. CRP <3 mg/dl and ESR <40 mm/h
  1. Discharge home with follow-up
  2. Repeat labs and evaluation if fever persists an additional 2 days
  3. Obtain Echocardiogram if peeling occurs (regardless of fever resolution)
2. CRP >3 mg/dl or ESR >40 mm/h
  1. Obtain additional criteria (requires 3 or more)
    1. Serum Albumin <3 g/dl
    2. Anemia
    3. Serum ALT increased
    4. White Blood Cell Count >12,000
    5. Platelet Count >450,000
    6. Sterile pyuria
  2. Three or more additional criteria present
    1. Treat as Kawasaki Disease
    2. Obtain Echocardiogram
  3. Less than three additional criteria
    1. Obtain Echocardiogram
    2. If Echocardiogram positive, treat as Kawasaki Disease
    3. If Echocardiogram negative, but fever persists, repeat the Echocardiogram

Management

Admission
Hydration
Obtain Rheumatology and Cardiology Consultation
Observe for and treat Congestive Heart Failure
Cardiac monitoring in all patients
Start treatment as soon as possible
1. Especially within 10 days of onset
2. Do not delay for Echocardiogram if diagnostic criteria are met
Aspirin
1. Postulated to reduce inflammation and thrombus formation
  1. However does not reduce coronary aneurysm formation
2. Dosing
  1. Initial: 20-25 mg/kg every 6 hours
  2. Later: 3-5 mg/kg/day once daily for 6-8 weeks
    1. Start after fever has resolved at least 2 days OR
    2. 14 days passes since onset of illness
  3. Longterm
    1. May be indicated indefinately if coronary anomalies are identified
    2. Precautions should be taken against Reye Syndrome if longterm Aspirin is used
      1. Influenza Vaccine
      2. Varicella Vaccine
      3. Post-exposure precautions
Intravenous Gamma Globulin (IVIG)
1. Dose: 2 g/kg infused over 8-12 hours
2. Must be given early in disease to be efficacious
3. Consider repeating for a second dose if still febrile after first dose
4. Risk of Hypotension and Seizures
5. Avoid live virus Vaccines for 11 months after IVIG
6. Efficacy
  1. Effect likely based on reducing Cytokines, antibodies and T-Cell activity
  2. Reduces Coronary Artery anomaly risk from 25% to 5%
  3. Reduces giant aneurysm risk to <1%
Corticosteroids
1. May be used in combination with IVIG to reduce the risk of coronary anomalies
2. Most indicated in the 10-20% of cases refractory to IVIG and Aspirin (see below)
3. Chen (2013) Heart 99(2): 76-82 [PubMed]
Refractory cases (10-20%, fever persists or recurs 36 hours after initial IVIG)
1. Repeat IVIG 2 g/kg
2. Consider Corticosteroids
3. Variable evidence for Infliximab (Remicade)
  1. Tremoulet (2014) Lancet 383(9930): 1731-8 [PubMed]

Complications
General

Early complications
1. Myocarditis
2. Pericarditis
3. Valvular insufficiency (esp. mitral insufficiency, and to a lesser extent Aortic Insufficiency)
4. Arrhythmia
5. Kawasaki Disease Shock Syndrome (7% of cases)
  1. Cardiovascular collapse often refractory to IVIG
  2. Manage with volume expanders and Vasopressors
Late complications (>1-2 weeks)
1. Coronary Artery aneurysm (see below)

Complications
Coronary Artery aneurysm

Incidence
1. Occurs in 20% of untreated Kawasaki's Disease
2. Occurs in 2% of treated Kawasaki's Disease
Mechanism: Coronary Artery Vasculitis
Occurs 2-4 weeks after onset of illness
Most aneurysms regress in 1-2 year
1. Spontaneously resolve in 33-66% of cases
Most common coronary arteries affected
1. Proximal left anterior descending artery
2. Proximal right Coronary Artery
Associated Risks
1. Subsequent stenosis
2. Thrombosis leading to Myocardial Infarction
3. Sudden Death
Risk Stratification
1. Risk Level 1: Normal coronary arteries on imaging
  1. May stop Aspirin at 8 weeks following onset
  2. No Physical Activity restrictions after first 6-8 weeks
  3. Life-long counseling on Cardiac Risk Factors every 5 years
    1. Long-term endothelial dysfunction risk
2. Risk Level 2: Transient coronary ectasia, dilation (resolves in first 6-8 weeks)
  1. Same approach as Risk Level 1
3. Risk Level 3: Coronary aneurysms 3-6 mm (Z-Score 3-7)
  1. Aspirin 3-5 mg/kg daily for >8 weeks and until aneurysm regresses
  2. Stress Test every 2 years before sports if age >10
  3. Annual cardiology follow-up Echocardiogram and Electrocardiogram
  4. Avoid contact or high-impact sports if on antiplatelet agents
4. Risk Level 4: coronary aneurysms >6 mm (large) or multiple
  1. Long-term Aspirin
  2. Warfarin (INR 2-2.5) or LMWH (Xa 0.5-1) for giant aneurysms
  3. Annual cardiac stress test
  4. Cardiology follow-up with Echocardiogram and Electrocardiogram every 6 months
  5. Cardiac angiogram 6-12 months after illness
  6. Avoid Collision Sports
5. Risk Level 5: Obstructed Coronary Artery aneurysms
  1. Includes recommendations for risk level 4
  2. Beta Blocker

References

Claudius in Majoewsky (2012) EM:Rap 12(11): 8-9
Pacheco and Rawani-Patel (2019) Crit Dec Emerg Med 33(5): 3-11
Dummer (2004) Progress Pediatr Cardiol 19:129-35 [PubMed]
Freeman (2006) Am Fam Physician 74:1141-50 [PubMed]
Newburger (2004) Pediatrics 114:1708-33 [PubMed]
Newburger (2004) Circulation 110(17): 2747-71 [PubMed]
Saguil (2015) Am Fam Physician 91(6): 365-71 [PubMed]